WO2018227886A1 - 新型吲哚胺2,3-双加氧化酶抑制剂 - Google Patents

新型吲哚胺2,3-双加氧化酶抑制剂 Download PDF

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WO2018227886A1
WO2018227886A1 PCT/CN2017/112547 CN2017112547W WO2018227886A1 WO 2018227886 A1 WO2018227886 A1 WO 2018227886A1 CN 2017112547 W CN2017112547 W CN 2017112547W WO 2018227886 A1 WO2018227886 A1 WO 2018227886A1
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group
compound
add
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aryl
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French (fr)
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张孝清
宋志春
包金远
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南京华威医药科技集团有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the field belongs to the field of anti-tumor drugs, and particularly relates to a highly effective IDO inhibitor, a preparation method and use thereof.
  • IDO Indoleamine 2,3-dioxygenase
  • IDO Indoleamine 2,3-dioxygenase
  • IDO is the only rate-limiting enzyme outside the liver that catalyzes the catabolism of tryptophan along the kynurenine pathway. It is widely distributed in humans and animals. Many tissues and cells. IDO can inhibit the proliferation of pathogenic microorganisms by reducing the concentration of tryptophan in the microenvironment; IDO is also closely related to neurological diseases, which can reduce the level of serotonin and cause depression, and can also cause quinolinic acid in the brain. The accumulation of neurotoxic metabolites; some evidence suggests that IDO is involved in the induction of immune tolerance.
  • IDO-expressing cells can suppress T cell responses and promote tolerance, so IDO inhibits T-cell immunity and anti-tumor immunity, and induces maternal-fetal immunity. Both tolerance and graft immune tolerance play important metabolic immunomodulatory effects. At present, IDO is an important drug discovery target and has become the most important small molecule regulatory target for anti-tumor immunotherapy.
  • IDO inhibitors are WO2016071293, WO2010005958, WO2014066834, WO2016155545, CN 103130735A and the like.
  • IDO inhibitors can be used to treat various major diseases such as tumors, Alzheimer's disease, depression and cataract.
  • major diseases such as tumors, Alzheimer's disease, depression and cataract.
  • IDO inhibitors can be used to treat various major diseases such as tumors, Alzheimer's disease, depression and cataract.
  • Another object of the invention is to provide a pharmaceutical composition of the guanamine 2,3-dioxygenase inhibitor and uses thereof.
  • the object of the invention can be achieved by the following measures:
  • R represents a hydrogen atom or m stands for 0-6;
  • X represents a substituted or unsubstituted aryl group, an aryl biaryl group, an aryl biaryl group, a heteroaryl biaryl group, or Wherein the Ar group described in X is independently optionally selected from substituted or unsubstituted aryl, arylbiaryl, heteroaryl;
  • M is independently selected from O, S, NH, C 1-4 alkylamino groups
  • Y represents a substituted or unsubstituted C 3-10 alkenyl group, a C 1-10 alkyl group, a C 3-8 cycloalkyl group, a phenyl group or Any of them;
  • W representative n represents an Arabic number from 0 to 6;
  • the substituents of the X, Ar, Y groups are each independently selected from a C 1-8 alkoxy group, a halogen, a C 1-6 ester group, an amino group, a C 1-6 alkylamino group, a trifluoromethyl group. base, One or more of them, wherein R represents a C 1-6 alkyl group.
  • the number of ring atoms of the aryl group or heteroaryl group involved in the aryl group, heteroaryl group, aryl aryl group, arylheteroaryl group, heteroarylheteroaryl group is 5 ⁇ 8.
  • the aryl biaryl group is a phenyl biphenyl group, and the aryl biaryl group is optionally selected from a phenyl bipyrazinyl group and a phenyl biimidazolyl group; and the heteroaryl biaryl group is 5 to a 6-membered ring containing a nitrogen-containing heteroaryl group having a 5- to 6-membered ring nitrogen-containing heteroaryl group;
  • heteroarylbiheteroaryl group is a pyrimidinylbipyrimidinyl group.
  • the substituent of Ar is F or trifluoromethyl.
  • Y is a substituted or unsubstituted C 4-6 alkyl group.
  • the present invention also provides a process for the preparation of a compound of the formula I and a salt thereof, but is not limited to the process described below. All starting materials are based on the group characteristics of the target molecule in accordance with the general formula and are prepared by methods in these routes, methods well known to those of ordinary skill in the art of organic chemistry, or purchased directly.
  • the compounds of the present invention can be synthesized by combining the following methods with synthetic methods known in the art of synthetic organic chemistry or related alteration methods recognized by those skilled in the art.
  • R as defined in the general formula I represents a hydrogen atom
  • the definition of X is the same as defined above in the specification, and the preparation scheme thereof is as follows:
  • the preparation method of the compound of the formula I' and its salt comprises the following steps:
  • a compound I' (wherein the compound of the formula is a hydrogen atom in the formula I) with a carbonyl diimidazole under the catalysis of an inorganic base to obtain a compound I'-1; It is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like.
  • Another object of the present invention is to provide a process for the preparation of the intermediate compound III, as follows:
  • R in the formula I represents a hydrogen atom
  • X represents a substituted or unsubstituted arylbiaryl group, an arylbiheteroaryl group, a heteroarylheteroaryl group, and the substituent is as defined above in the specification.
  • the scheme for the corresponding intermediate III of Preparation I is as follows:
  • P and Q each independently represent a substituted or unsubstituted aryl or heteroaryl group, and the substituent has the same definition as the substituent in the X group above.
  • the preparation of Compound III can be carried out by referring to the methods of Examples 3 to 6.
  • the preparation of the compound III-a in the second scheme comprises the following steps:
  • Compound III-1, compound III-2 is obtained by the reaction of an inorganic base and a palladium catalyst.
  • the inorganic base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide
  • the palladium catalyst is selected from tetrakis phenylphosphorus palladium.
  • Step 1 using compound III-3 and compound III-4 to react under the action of an inorganic base to obtain compound III-5;
  • Step 2 Compound III-5 is reduced by a reducing reagent to obtain III-b.
  • the inorganic base is arbitrarily selected from one or more of cesium carbonate, potassium t-butoxide, sodium methoxide, sodium hydroxide or potassium hydroxide, and the reducing agent may be hydrazine hydrate, activated carbon and FeCl.
  • the combination of 3 can also be hydrogenated and reduced under the catalysis of Pd/C.
  • Ar' is an aryl group or a heteroaryl group.
  • the protection and deprotection reaction of the intermediate group it can be carried out by referring to the scheme in the first scheme, and specifically, the group protection and deprotection in the embodiment 11 or the embodiment 13 can be carried out.
  • the compound III-5' and the compound III-5-1' can also be prepared by using a fluorine-containing nitro compound and a diol compound III-4' or a diamine compound.
  • III-4" is respectively obtained by the reaction of an inorganic base, which may be potassium t-butoxide or sodium t-butoxide, etc., and the preparation route thereof is as shown in Scheme 4-1, wherein the definition of Ar and Ar' It is the same as defined in Scheme 4. Specifically, refer to Step 1 of Preparation of Compound 28 in Example 12. This is carried out or with reference to the corresponding steps of Example 19.
  • the preparation scheme can be carried out by referring to the case where M represents an O atom, and can be prepared according to the scheme in Scheme 3, Scheme 4 or Scheme 4-1.
  • the corresponding hydroxyl group of the compound III-3, III-3-1 or the compound III-4' is replaced with a thiol group according to the structure of the target molecule, and a suitable starting compound is selected for the reaction, thereby obtaining when the M represents a sulfur atom.
  • Intermediate Compound III Compound The specific reaction can be carried out with reference to Example 20 or 21.
  • the method of introducing the substituent on the Y group can be carried out by referring to the scheme of the compound 1-43 of Example 15. On the basis that the substituent of the Y group is an amino group, it is obtained by reacting with a corresponding substituent compound containing a bromine-reactive functional group.
  • Option 6 contains the following steps:
  • the amino-protected diamine compound 5 and the dicarboxylic acid compound V are added to an organic solvent, and an amide reaction is carried out under the action of an amidation catalyst to obtain a compound IV, and then the protective group is removed to obtain a compound III-e.
  • amidation catalyst in Scheme 6 is optionally selected from one or a combination of HBTU, HATU, HOBT, EDCI, HOBT, DCC, DIEA.
  • Option 7 contains the following steps:
  • Option 8 contains the following steps:
  • the amino-protected diamine compound 5 and the compound V-1 are added to an organic solvent, and an amide reaction is carried out under the action of an amidation catalyst to obtain a compound V-2, and then the protective group is removed to obtain a compound III-f.
  • the amino-protected diamine compound 5 and Fmoc-alanine (compound I-9-1) are added to an organic solvent, and an amide reaction is carried out under the action of an amidation catalyst to obtain a compound V-2, which is then removed for protection.
  • the base can be. Further, the preparation thereof can be carried out by referring to the method of the compound I-9 in the examples.
  • the intermediate compound III when the intermediate compound III has the formula M, it represents NH, an alkylamine,
  • the preparation scheme can be carried out according to the scheme 3, the scheme 4 or the scheme 6;
  • the preparation scheme can be carried out by referring to the case where M represents an O atom, and reference can be made to the scheme III.
  • the preparation method in Scheme 4 or Scheme 4-1 replacing the corresponding hydroxyl group in the compound III-3, III-3-1 or the compound III-4' with a hydroxyl group, an NH group, a mercapto group or an alkylamine according to the structure of the target molecule.
  • the corresponding two different groups are reacted with a suitable starting compound to obtain an intermediate III compound having an asymmetric M group on both sides in accordance with the structural characteristics of the target molecule.
  • the specific reaction can be carried out with reference to Example 27 or 28.
  • the intermediate or target molecule of each of the above schemes comprises an arylheteroaryl or an arylbiaryl or a heteroarylbiaryl group, which can be obtained by a coupling reaction. The corresponding steps are carried out.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or isomer thereof as active ingredient, together with one or more pharmaceutically acceptable carriers , thinner or excipient.
  • the pharmaceutical composition preferably contains, as an active ingredient, a pharmaceutically acceptable salt of the formula I or formula II in a weight ratio of from 1% to 99%, more preferably from 5% to 85% by weight of the active ingredient.
  • Aryl means an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a fully conjugated pi-electron system.
  • Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring.
  • the aryl group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably one, two or three, still more preferably one or two, independently selected from lower alkyl, trihaloalkyl, halogen, hydroxy , lower alkoxy, fluorenyl, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thioamino Formyl, C-amido, N-acylamino, nitro, N-sulfonylamino, S-sulfonylamino.
  • the aryl group is a 5-membered monocyclic aryl group, a 6-membered monocyclic aryl group.
  • Heteroaryl means a monocyclic or fused ring radical of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C In addition, it has a fully conjugated ⁇ -electron system.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two.
  • Non-limiting examples of unsubstituted heteroaryl sites are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, indole, tetrazole, triazine and oxazole; preferably,
  • the heteroaryl group is a nitrogen-containing 5-membered monocyclic heteroaryl group and a nitrogen-containing 6-membered monocyclic heteroaryl group.
  • Alkyl means a saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, including both straight-chain and branched-chain groups (the range of numbers referred to in this application, such as “1-20", refers to the group, In the case of an alkyl group, it may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms).
  • the alkyl group in the present invention contains an "alkylene group".
  • An alkyl group having 1 to 6 carbon atoms is referred to as a lower alkyl group. When the lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group.
  • the alkyl group is a medium size alkyl group having from 1 to 10 carbon atoms, such as methyl, ethyl, ethylene, propyl, propylene, 2-propyl, n-butyl, iso Butyl, butylene, tert-butyl, pentyl and the like.
  • the alkyl group is a lower alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, a butylene group, an isobutyl group or a t-butyl group.
  • the alkyl group can be substituted or unsubstituted.
  • Alkoxy means -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • Alkoxy preferably includes alkoxy groups of 1 to 10 carbon atoms, more preferably alkoxy groups of 1 to 6 carbon atoms; representative examples include, but are not limited to, methoxy, ethoxy, propoxy, Butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • An “isomer” is selected from the group consisting of a cis isomer, a trans isomer or a mixture of cis and trans isomers.
  • Alkenyl means an unsaturated aliphatic hydrocarbon radical of from 2 to 20 carbon atoms containing at least one carbon to carbon double bond, including both straight chain and branched chain groups. More preferably, the alkenyl group is a medium-sized alkenyl group having 2 to 10 carbon atoms, and more preferably a C 2 - 6 alkenyl group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Carboxyl means -COOH.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 8 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms, most preferably a cyclopropyl group.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Niro means -NO 2 .
  • alkylamine group The group, alkyl group is as defined above, preferably a C 1-4 alkyl group.
  • Ester group means a functional group of an ester in a carboxylic acid derivative, -COOR (R is generally a non-H group such as an alkyl group, and the alkyl group is as defined above), for example, when a carbon atom of an alkyl group is contained therein When the number is from 1 to 6, the ester group may be abbreviated as a C 1-6 ester group.
  • the two sides of Y may be symmetrical or asymmetric, that is, M on both sides connected to Y may represent the same group, or may represent different groups, and the corresponding Ar, the two sides may be the same or different.
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid And perchloric acid, etc., organic acids such as, but not limited to, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid , methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, Mandelic acid, succinic acid or malonic acid.
  • “Pharmaceutical composition” refers to one or more of the compounds described herein or their pharmaceutically acceptable salts, isomers and prodrugs, and the like. Mixture with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • “Pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • excipients include, without limitation, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose. , water, syrup and methyl cellulose.
  • compositions may also contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring Agent.
  • lubricants such as talc, magnesium stearate and mineral oil
  • wetting agents such as talc, magnesium stearate and mineral oil
  • emulsifying and suspending agents such as methyl benzoate and hydroxypropyl benzoate
  • preservatives such as methyl benzoate and hydroxypropyl benzoate
  • sweeteners and flavoring Agent sweeteners and flavoring Agent.
  • HBTU The Chinese name of HBTU is benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate
  • HATU Chinese name is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • the present invention also provides the use of the above formula I and a pharmaceutically acceptable salt or isomer thereof for the preparation of a medicament for the disease associated with indoleamine 2,3-dioxygenase (IDO), in particular It is used in the treatment of a variety of major diseases such as tumors, Alzheimer's disease, depression, cataracts.
  • the tumor is preferably liver cancer, lung cancer, or ovarian cancer.
  • the results of preliminary drug activity studies indicate that the compounds of the present invention have good IDO inhibitory activity against human hepatoma cell lines, human large cell lung cancer cell lines, human ovarian cancer cell lines, human small cell lung cancer cell lines, and human non-small cell lung cancer cell lines.
  • the growth of various human tumor cell lines has obvious inhibitory effects, and its comprehensive effect is better than INCB024360.
  • the pharmacokinetic test also showed that the compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect. Compared with INCB024360, the compound of the present invention has better pharmacokinetics in the case of a relatively higher or even higher drug effect.
  • the dynamic nature has great medicinal value and broad market prospects.
  • Step 1 Take 405 mg of p-aminophenylboronic acid, 400 mg of 2-amino-5-bromo-3-methoxypyrazine, 552 mg of potassium carbonate, 30 mg of tetratriphenylphosphine palladium, 10 ml of DMF and 1 ml of water, replace nitrogen, and heat up to The reaction was carried out at 100 ° C overnight, and the reaction of the starting material was completed by TLC. The reaction mixture was taken to room temperature. Water and ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. .
  • Step 2 Take 100 mg of compound I-16-1, add 10 ml of DMF to dissolve, add 190 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml * 3), and the organic layer was combined, dried over anhydrous sodium sulfate.
  • Step 1 Take 550 mg of m-aminophenylboronic acid, 445 mg of 2-bromo-5-chloro-4-fluoroaniline, 552 mg of potassium carbonate, 30 mg of tetrakistriphenylphosphine palladium, 10 ml of DMF and 1 ml of water, replace nitrogen, and raise the temperature to 100 ° C. After overnight, the basic reaction of the starting material was completed by TLC, and the mixture was cooled to room temperature. Water and ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 2 Take 120 mg of compound I-17-1, add 10 ml of DMF to dissolve, add 205 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml * 3), and the organic layer was combined, dried over anhydrous sodium sulfate.
  • Step 1 Take 550mg of m-aminophenylboronic acid, 412mg of 3-bromo-4-chloroaniline, 552mg of potassium carbonate, 30mg of tetratriphenylphosphine palladium, 10ml of DMF and 1ml of water, replace nitrogen, heat up to 100 ° C for overnight reaction, TLC detection The starting material was completely reacted to room temperature, water and ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 2 Take 160 mg of compound I-18-1, add 10 ml of DMF to dissolve, add 300 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml*3).
  • Step 1 Take 1.0 g of 3-bromo-4-chloroaniline, 3.6 g of pinacol borate, 2.0 g of potassium carbonate, 300 mg of tetratriphenylphosphine palladium, 10 ml of DMF and 1 ml of water, replace nitrogen, and warm to 100 ° C. After reacting overnight, the basic reaction of the starting material was completed by TLC, and the mixture was cooled to room temperature. Water and ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 2 Take 600 mg of compound I-19-1, 250 mg of 3-bromo-4-chloroaniline, 330 mg of potassium carbonate, 30 mg of tetrakistriphenylphosphine palladium, 10 ml of DMF and 1 ml of water, replace nitrogen, and warm to 100 ° C overnight.
  • the basic reaction of the starting material was completely determined by TLC, and the mixture was cooled to room temperature. Water and ethyl acetate were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 3 Take 150 mg of compound I-19-2, add 10 ml of DMF to dissolve, add 200 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml*3).
  • Step 1 Take 1.4g of p-nitrophenol, 1.05g of 1,4-dibromobutane, 2.1g of potassium carbonate, 20ml of DMF, heat up to 120 ° C for 3h, TLC detection of the basic reaction of the raw material is complete, down to room temperature, add water After that, a large amount of solid precipitated, suction filtration, water rinsing, draining and drying to obtain 1.2 g of compound I-7-1.
  • Step 2 Take 1.2g of the above compound I-7-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, and warm up to 80 ° C and then add dropwise 5ml hydrazine hydrate, TLC detection of the basic reaction of the raw material is complete, hot and assisted filtration with diatomaceous earth, retain the filtrate, remove most of the solvent under reduced pressure, add 20ml of methanol to be beaten, suction filtration, drying to obtain 0.6g of compound I-7-2 .
  • Step 3 Take 200 mg of compound I-7-2, add 10 ml of DMF to dissolve, add 300 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml * 3), and the organic layer was combined, dried over anhydrous sodium sulfate.
  • Step 1 Take 1.6g of 2-fluoro-4-nitrophenol, 1.05g of 1,4-dibromobutane, 2.1g of potassium carbonate, 20ml of DMF, heat up to 120 ° C for 3h, TLC detection of the basic reaction of the raw materials is complete, down to After adding water at room temperature, a large amount of solid precipitated, suction filtration, water rinsing, draining and drying to obtain 1.3 g of compound I-10-1.
  • Step 2 Take the above 1.3 g of compound I-10-1, 0.6 g of ferric chloride, 0.25 g of activated carbon, 60 ml of tetrahydrofuran, and then warm to 80 ° C, then add 5 ml of hydrazine hydrate, and the basic reaction of the raw material is completely detected by TLC.
  • the algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to obtain 0.8 g of compound I-10-2.
  • Step 3 Take 200 mg of compound I-10-2, add 10 ml of DMF to dissolve, add 260 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml*3), and then evaporated, evaporated, evaporated
  • Step 1 Take 1.4 g of p-nitrophenol, 1.0 g of 1,4-dibromo-2-butene, 2.1 g of potassium carbonate, 20 ml of DMF, and heat up to 120 ° C for 3 h.
  • the basic reaction of the starting material by TLC is completely reduced to room temperature.
  • Step 2 Take 1.1g of the above compound I-11-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat to 80 ° C, and then add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw material is complete, hot and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be slurried, filtered, and dried to give 0.62 g of Compound I-11-2.
  • Step 3 Take 200 mg of compound I-11-2, add 10 ml of DMF to dissolve, add 300 mg of compound 1, stir at room temperature, check the reaction of the starting material completely by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid The ethyl ester was extracted (20 ml * 3), and the organic layer was combined, dried over anhydrous sodium sulfate.
  • Step 1 Take 2.2 g of 2-bromo 4-nitrophenol, 1.05 g of 1,4-dibromobutane, 2.1 g of potassium carbonate, 20 ml of DMF, and heat up to 120 ° C for 3 h. The basic reaction of the starting material is completely reduced by TLC. After adding water at room temperature, a large amount of solid precipitated, suction filtration, water rinsing, draining and drying to obtain 1.8 g of compound I-26-1.
  • Step 2 Take the above 1.8 g of compound I-26-1, 0.9 g of ferric chloride, 0.4 g of activated carbon, 60 ml of tetrahydrofuran, and raise the temperature to 80 ° C, then add 6 ml of hydrazine hydrate, and the basic reaction of the raw material is completely detected by TLC.
  • the algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be slurried, filtered, and dried to give 1.28 g of Compound I-26-2.
  • Step 3 Take 1.28g of compound I-26-2, 3.2g of 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester, 2.4g of potassium carbonate, 300mg of tetratriphenylphosphine palladium, 50 ml of DME and 5 ml of water, replacing nitrogen, heating to 100 ° C overnight reaction, TLC detection of the basic reaction of the starting material completely, down to room temperature, adding water and ethyl acetate, liquid separation, drying the organic phase anhydrous sodium sulfate, decompression to dry, Column chromatography gave 0.5 g of compound I-26-3.
  • Step 4 Take 0.5g of compound I-26-3, add 10ml of DMF to dissolve, add 0.37g of compound 1, stir at room temperature, check the raw material reaction by TLC, add a few drops of triethylamine to the reaction droplet, add 50ml of water, The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc.
  • Step 5 Take 220 mg of compound I-26-4, dissolve it with 10 ml of tetrahydrofuran, add 1 ml of 6 mol/L hydrochloric acid solution, react at room temperature, check the basic reaction of the starting material completely by TLC, add water and ethyl acetate, and separate the organic phase. After drying with sodium sulfate, the mixture was evaporated to dryness.
  • Step 1 is the same as compound I-26 synthesis step 1, step 2.
  • Step 3 Take 1.2 g of compound I-26-2, 4.0 g of 1-trityl-4-imidazolium borate pinacol ester, 2.4 g of potassium carbonate, 300 mg of tetratriphenylphosphine palladium, 50 ml of DME and 5 ml of water. The nitrogen gas was replaced and the temperature was raised to 100 ° C overnight. The basic reaction of the starting material was completely determined by TLC, and the mixture was cooled to room temperature. Water and ethyl acetate were added, and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. g Compound I-27-1.
  • Step 4 Take 0.8g of compound I-27-1, add 10ml of DMF to dissolve, add 0.37g of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplet, add 50ml of water, The organic phase was combined with ethyl acetate (MgSO4).
  • Step 5 Take 250 mg of compound I-27-2, dissolve it with 10 ml of tetrahydrofuran, add 0.5 ml of trifluoroacetic acid, and react at room temperature. The basic reaction of the starting material is complete by TLC, water and ethyl acetate are added, and the organic phase is anhydrous sulfuric acid. After drying the sodium, the mixture was evaporated to dryness.
  • Step 1 Take 1.04g of 2-fluoro-5-nitrobenzotrifluoride, 290mg of 1,4-cyclohexanediol, 0.55g of potassium t-butoxide, 20ml of DMF, and react at room temperature. The basic reaction of the raw materials is completely detected by TLC, and water is added. After that, a large amount of solid precipitated, suction filtration, water rinsing, draining and drying to obtain 1.2 g of compound I-28-1.
  • Step 2 Take 1.2g of the above compound I-28-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat to 80 ° C, and then add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw material is complete, hot and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.6 g of Compound I-28-2.
  • Step 3 Take 200 mg of compound I-28-2, add 10 ml of DMF to dissolve, add 200 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml * 3), and the organic layer was combined, dried over anhydrous sodium sulfate.
  • Step 1 Take 1.6g of 3,4-difluoronitrobenzene, 1.05g of 2-Boc-amino-1,4-butanol, 2.2g of potassium t-butoxide, 20ml of DMF, and determine the basic reaction of the starting material by TLC, adding water. After that, a large amount of solid precipitated, suction filtration, water rinsing, draining and drying to obtain 1.2 g of compound I-36-1.
  • Step 2 Take 1.2g of the above compound I-36-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat to 80 ° C, and then add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw material is complete, hot and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.6 g of Compound I-36-2.
  • Step 3 Take 600 mg of compound I-36-2, add 10 ml of DMF to dissolve, add 575 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml * 3), and the organic layer was combined, dried over anhydrous sodium sulfate.
  • Step 4 Take 280 mg of compound I-36-3, dissolve it with 20 ml of dichloromethane, add 2 ml of trifluoroacetic acid, and react at room temperature. The basic reaction of the starting material is complete by TLC. Water is added, and the organic phase is dried over anhydrous sodium sulfate. The mixture was depressurized to dryness to give 10 mg of Compound I-36.
  • Step 1 Take 10ml of tetrahydrofuran, stir at 0 ° C, add 38mg of lithium tetrahydrogenate in batches, 135mg of compound I-36-3 is added to the reaction flask with 5ml of tetrahydrofuran, and the basic reaction of the raw materials is completely detected by TLC. After the saturated ammonium chloride solution was quenched, water and ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 Take 100 mg of compound I-36, dissolve it with 10 ml of tetrahydrofuran, stir at 0 ° C, add 100 mg of triethylamine, dissolve 40 mg of 5-bromo-2,4-dichloropyrimidine with 5 ml of tetrahydrofuran, add dropwise In the reaction flask, the starting material was completely reacted by TLC, water and ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 Take 3.0 g of N-Boc m-phenylenediamine, add 20 ml of dichloromethane, add 0.72 g of triphosgene at low temperature, and transfer to a normal temperature reaction. TLC was used to detect the reaction of the starting material, and 200 ml of water was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 ml*3). The organic phase was combined, dried over anhydrous sodium sulfate and evaporated to dryness. -3-1.
  • Step 2 1.0 g of the compound I-3-1 was taken, dissolved in 10 ml of dichloromethane, and 2 ml of trifluoroacetic acid was added dropwise thereto, and stirred at room temperature. The TLC detected that the starting material was completely reacted, and a white solid, 0.4 g, of compound I-3-2 was obtained.
  • Step 3 Take 0.2 g of compound I-3-2, add 10 ml of ethyl acetate to dissolve, 0.4 g of compound 1, stir at room temperature, detect by TLC until the reaction of the starting material is complete, add 1 ml of TEA, add 100 water, extract 50 ml of EA, no After drying with sodium sulfate, the mixture was evaporated to dryness.
  • Step 1 Take 2.0 g of N-Boc m-phenylenediamine, 0.56 g of succinic acid, 7.2 g of HBTU, DMF 20 ml, 1 ml of triethylamine, and stir at room temperature for 5.0 h. The reaction of the starting material was completely detected by TLC, and 300 ml of water was added to the reaction mixture, and a large amount of solid was precipitated to give 1.5 g of a white solid compound I-4-1.
  • Step 2 Take 1.5 g of compound I-4-1, add 20 ml of DCM to dissolve, add 2 ml of TFA at low temperature, and stir at room temperature overnight.
  • the TLC was used to detect the reaction of the starting material completely, and a solid precipitated. After adding water to dissolve, it was extracted once with EA, and the aqueous phase was adjusted to pH 8 to 9 with aqueous ammonia, and a large amount of solid was precipitated, and 0.3 g of an off-white solid compound I-4-2 was obtained.
  • Step 3 The obtained compound I-4-2 was dissolved in 20 ml of EA, and 0.4 g of Compound 1 was added, and stirred at room temperature.
  • the basic reaction of the TLC was carried out, and 1 ml of TEA was added dropwise, and 100 ml of water was added thereto, and extracted with 50 ml of EA, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 Take 2.0 g of N-Boc m-phenylenediamine, dissolve it with 10 ml of tetrahydrofuran, add 1 ml of triethylamine, stir at 0 ° C, add 0.6 g of 4-(chlorosulfonyl)benzoic acid, and completely react with TLC. To the reaction liquid, 300 ml of water was added, and a large amount of solid was precipitated to give 1.5 g of a white solid compound I-21-1.
  • Step 2 Take 2.0g of compound I-21-1, 1.06g of N-Boc m-phenylenediamine, 3.8g of HBTU, DMF 20ml, 1ml of triethylamine, stir at room temperature 5.0h. The reaction of the starting material was completely detected by TLC, and 300 ml of water was added to the reaction mixture, and a large amount of solid was precipitated, thereby giving 1.5 g of a white solid compound I-21-2.
  • Step 3 Take 1.5 g of compound I-21-2, add 20 ml of DCM to dissolve, add 2 ml of TFA at low temperature, and stir at room temperature overnight. TLC detected the reaction of the starting material completely, and a solid precipitated. After adding water and clearing, it was extracted once with EA. The aqueous phase was adjusted to pH 8 to 9 with aqueous ammonia, and a large amount of solid was precipitated, and 0.3 g of an off-white solid compound I-21-3 was obtained.
  • Step 4 Take 600 mg of compound I-21-3, add 10 ml of DMF to dissolve, add 600 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. Ethyl acetate (20 ml*3), EtOAc (EtOAc m.
  • Step 1 Take 1.6g of 3,4-difluoronitrobenzene, 0.44g of 1,4-butanediamine, 1.1g of potassium t-butoxide, 20ml of DMF. The basic reaction of the raw materials is completely determined by TLC. After adding water, there is a large amount of solid. Precipitation, suction filtration, water rinsing, draining and drying gave 1.2 g of Compound I-30-1.
  • Step 2 Take 1.2g of the above compound I-30-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat up to 80 ° C, add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw material, heat and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.6 g of Compound I-30-2.
  • Step 3 Take 600 mg of compound I-30-2, add 10 ml of DMF to dissolve, add 300 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. Ethyl acetate was extracted (20 ml * 3), and the organic phase was combined, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 Take 1.04g of 2-fluoro-5-nitrobenzotrifluoride, 0.66g of 1,4-butanedithiol, 0.56g of potassium t-butoxide, 20ml of DMF, and determine the basic reaction of the raw material by TLC. After adding water, A large amount of solid precipitated, suction filtered, water rinsed, dried and dried to give 1.0 g of Compound I-24-1.
  • Step 2 Take 1.0g of the above compound I-24-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat to 80 ° C, and then add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw materials, heat and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.6 g of Compound I-24-2.
  • Step 3 Take 600 mg of compound I-24-2, add 10 ml of DMF to dissolve, add 450 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml*3).
  • Step 1 Take 1.05g of 2-fluoro-3-trifluoromethyl-5-nitropyridine, 0.66g of 1,4-butanedithiol, 0.56g of potassium t-butoxide, 20ml of DMF, and complete the basic reaction of the raw materials by TLC. After adding water, a large amount of solid precipitated, suction filtration, water rinsing, draining and drying to obtain 1.1 g of compound I-46-1.
  • Step 2 Take 1.1g of the above compound I-46-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat up to 80 ° C, add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw material, heat and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.5 g of Compound I-46-2.
  • Step 3 Take 500 mg of compound I-46-2, add 10 ml of DMF to dissolve, add 450 mg of compound 1, stir at room temperature, and test the raw materials by TLC. The reaction was completed, a few drops of triethylamine were added to the reaction liquid, 50 ml of water was added, and the mixture was extracted with ethyl acetate (20 ml*3), and the organic phase was combined, dried over anhydrous sodium sulfate and evaporated to dryness. An off-white solid I-46.
  • Step 1 Take 1.4g of compound I-10, 1.05g of carbonyldiimidazole, 0.86g of potassium carbonate, 20ml of tetrahydrofuran, and raise the temperature to 50 ° C. The basic reaction of the raw material is completely detected by TLC. After adding water, a large amount of solid precipitates and is filtered. Water rinse, drain and dry to obtain 1.2g compound I-32-1.
  • Step 2 Take 1.2 g of the above compound I-32-1, dissolve 60 ml of tetrahydrofuran, add 1.6 g of compound 2, 2.5 g of sodium borohydride, and raise the temperature to 50 ° C. The basic reaction of the raw material is completely determined by TLC, and the reaction is repeated under reduced pressure. Part of the solvent, water and ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 3 Take 600 mg of compound I-32-2, add 10 ml of tetrahydrofuran, add 2 ml of hydrazine hydrate, stir at room temperature, completely react with TLC to detect the reaction, add 50 ml of water, extract with ethyl acetate (20 ml * 3), and combine organic The residue was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 Take 2.0 g of N-Boc p-phenylenediamine, 0.56 g of 4-(N-tert-butoxycarbonylamino)benzoic acid, 7.2 g of HBTU, DMF 20 ml, 1 ml of triethylamine, and stirred at room temperature for 5.0 h. The reaction of the starting material by TLC was completed, and 300 ml of water was added to the reaction mixture, and a large amount of solid was precipitated to give 1.5 g of white solid compound I-5-1.
  • Step 2 Take 1.5 g of compound I-5-1, add 20 ml of DCM to dissolve, add 2 ml of TFA at low temperature, and stir at room temperature overnight. The TLC was used to detect the reaction of the starting material completely, and a solid precipitated. After the solution was dissolved in water, it was extracted once with EA. The aqueous phase was adjusted to pH -8 to 9 with aqueous ammonia, and a large amount of solid was precipitated to give 0.3 g of an off-white solid compound I-5-2.
  • Step 3 The obtained Compound I-5-2 was dissolved in 20 ml of EA, and 0.4 g of Compound 1 was added, and stirred at room temperature. The basic reaction of TLC was complete, and 1 ml of TEA was added dropwise, 100 ml of water was added, 50 ml of EA was extracted, dried over anhydrous sodium sulfate, and then dried to dryness. Compound I-5.
  • Step 1 Take 2.0 g of N-Boc m-phenylenediamine, 0.56 g of 4-(N-tert-butoxycarbonylamino)phenylacetic acid, 7.2 g of HBTU, DMF 20 ml, 1 ml of triethylamine, and stir at room temperature for 5.0 h. The reaction of the starting material by TLC was completed, and 300 ml of water was added to the reaction mixture, and a large amount of solid was precipitated to give 1.5 g of white solid compound I-6-1.
  • Step 2 Take 1.5 g of compound I-6-1, add 20 ml of DCM to dissolve, add 2 ml of TFA at low temperature, and stir at room temperature overnight. The TLC was used to detect the reaction of the starting material completely, and a solid precipitated. After the solution was added with water, the mixture was extracted once with EA, and the aqueous phase was adjusted to pH 8 to 9 with aqueous ammonia. A large amount of solid was precipitated, and 0.3 g of an off-white solid compound I-6-2 was obtained.
  • Step 3 The obtained Compound I-6-2 was dissolved in 20 ml of EA, and 0.4 g of Compound 1 was added thereto, and stirred at room temperature.
  • the TLC was used to detect the basic reaction, and 1 ml of TEA was added dropwise, and 100 ml of water was added thereto, and extracted with 50 ml of EA, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 Take 2.0 g of N-Boc m-phenylenediamine, 3.0 g of Fmoc-alanine, 7.2 g of HBTU, DMF 20 ml, 1 ml of triethylamine, and stir at room temperature for 5.0 h. The reaction of TLC was completed, and 5 ml of piperidine was added to the reaction solution to remove the Fmoc protecting group. After the reaction, water and ethyl acetate were added, and the mixture was separated, dried over anhydrous sodium sulfate and then evaporated to dryness. White solid compound I-9-1.
  • Step 2 Take 0.8 g of compound I-9-1, 3.0 g of 3-(N-tert-butoxycarbonylamino)benzoic acid, 7.2 g of HBTU, DMF 20 ml, 1 ml of triethylamine, and stirred at room temperature for 5.0 h. The reaction of the starting material was completely detected by TLC, and 300 ml of water was added to the reaction mixture, and a large amount of solid was precipitated, and it was taken to give 1.5 g of white solid compound I-9-2.
  • Step 3 Take 1.5 g of compound I-9-2, add 20 ml of DCM to dissolve, add 2 ml of TFA at low temperature, and stir at room temperature overnight. TLC detected the reaction of the starting material completely, and solid precipitated. After adding water and clearing, it was extracted once with EA. The aqueous phase was adjusted to pH 8-9 with aqueous ammonia, and a large amount of solid was precipitated, and 0.3 g of an off-white solid compound I-9-3 was obtained.
  • Step 3 The obtained Compound I-9-3 was dissolved in 20 ml of EA, and 0.4 g of Compound 1 was added, and stirred at room temperature.
  • the basic reaction of TLC was carried out, and 1 ml of TEA was added dropwise, and 100 ml of water was added thereto, and extracted with 50 ml of EA, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 1 Compound I-50-1 was synthesized with reference to compound I-30-1.
  • Step 2 Take 1.2g of compound I-50-1, 10ml of DMF is dissolved, placed at 0 ° C, add 0.5g of sodium hydrogen, after 0.5h of reaction, add 2.0g of methyl iodide, continue the reaction for 2h, TLC detection of the basic reaction of the raw materials After adding 50 ml of water and extracting with ethyl acetate (20 ml*3), the organic phase was combined, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Step 3 Take the above 1.15g of compound I-50-2, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat up to 80 ° C, add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw materials, heat and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.6 g of Compound I-50-3.
  • Step 4 Take 600 mg of compound I-50-3, add 10 ml of DMF to dissolve, add 730 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml*3).
  • Step 1 Take 1.6g of 3,4-difluoronitrobenzene, 0.45g of 4-amino-1-butanol, 1.1g of potassium t-butoxide, 20ml of DMF. The basic reaction of the raw materials is completely determined by TLC. After adding water, there are a large number of The solid was precipitated, suction filtered, washed with water, dried and dried to give 1.15 g of Compound I-53-1.
  • Step 2 Take the above 1.15g of compound I-53-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat up to 80 ° C, then add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw materials, heat and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.6 g of Compound I-53-2.
  • Step 3 Take 600 mg of compound I-53-2, add 10 ml of DMF to dissolve, add 791 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. The ethyl ester was extracted (20 ml * 3), and the organic layer was combined, dried over anhydrous sodium sulfate.
  • Step 1 Take 1.6g of 3,4-difluoronitrobenzene, 0.53g of 4-mercapto-1-butanol, 1.1g of potassium t-butoxide, 20ml of DMF. The basic reaction of the raw materials is completely determined by TLC. After adding water, there are a large number of The solid was precipitated, suction filtered, washed with water, dried and dried to give 1.2 g of Compound I-54-1.
  • Step 2 Take the above 1.2g of compound I-54-1, 0.6g of ferric chloride, 0.25g of activated carbon, 60ml of tetrahydrofuran, heat to 80 ° C, add 5ml of hydrazine hydrate, TLC detection of the basic reaction of the raw material, heat and silicon The algae was assisted by filtration, the filtrate was retained, most of the solvent was removed under reduced pressure, and 20 ml of methanol was added to be beaten, filtered, and dried to give 0.6 g of compound I-54-2.
  • Step 3 Take 600 mg of compound I-54-2, add 10 ml of DMF to dissolve, add 800 mg of compound 1, stir at room temperature, check the reaction of the starting material by TLC, add a few drops of triethylamine to the reaction droplets, add 50 ml of water, use acetic acid. Ethyl acetate (20 ml * 3) was combined.
  • Test Example 1 Determination of the inhibitory activity of the compound on IDO1:
  • test examples are not intended to limit the present invention, and the following are the inhibitory activities of some of the compounds of the present invention against IDO1 enzyme at a concentration of 10 ⁇ M and 1 ⁇ M.
  • the structural formula of the compound is as shown in the above examples of the specification.
  • Multi-function microplate reader (Cat: M5, Molecular Devices)
  • Inhibition rate (OD positive - OD sample ) / (OD positive - OD negative ) * 100%
  • This experiment detects the inhibitory activity of the test compound on IDO1 enzyme at 10 ⁇ M and 1 ⁇ M. Each dilution concentration is a duplicate well test. The final concentration of DMSO in the control reaction system is 1%, and the inhibition rates at two concentrations are tested twice. The average value and the experimental results are shown in the following table. The results show that the compound of the present application shows a good inhibitory activity against the IDO1 protease.
  • This experiment detects the inhibitory activity of the test compound on IDO1 enzyme.
  • Test Example 2 Determination of IC50 value of compound in vitro cytotoxicity
  • Cytotoxicity IC50 values of the compounds of the present application against eight tumor cell lines were tested using the CCK-8 assay kit.
  • NCI-H460 human large cell lung cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • SMMC-7721 human liver cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • SK-OV-3 human ovarian cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • NCI-H446 human small cell lung cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • A549 human non-small cell lung cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • HepG2 human hepatoma cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • OVCAR-3 human ovarian cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • the compound of the invention was diluted in DMSO to a final concentration of 10 mM.
  • test compound was diluted with the medium to the corresponding concentration of action set, and the cells were added at 25 ⁇ l/well.
  • the final concentration of the compound was started from 100 ⁇ M, diluted 4 fold, 10 concentration points, and duplicate wells were tested.
  • tumor cell growth inhibition rate % [(Ac-As) / (Ac-Ab)] ⁇ 100%
  • the compounds of the present invention have obvious inhibitory effects on the growth of various human tumor cell lines, and the effect is better than INCB024360.
  • the pharmacokinetic tests of the compounds I-10, I-40 and the compound INCB024360 of the present application were carried out to study their pharmacokinetic behavior in rats, and their pharmacokinetic characteristics were evaluated.
  • mice 36 (male and female) SPF-class SD rats were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., among which 30 (male and female) healthy SD rats with good physical examination and no abnormality were used. In the study.
  • Blood was collected by jugular vein puncture, and each sample was collected about 0.25 mL. Heparin sodium was anticoagulated. The time of blood collection was as follows:
  • Oral administration group before administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration.
  • Plasma samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis. The plasma samples were analyzed by the laboratory analysis department using LC-MS/MS for the content of the test compound in the rat plasma. The LLOQ of the test substance was 1 ng/mL.
  • the pharmacokinetic parameters ANU 0-t , AUC 0-C , MRT 0-T and Cmax of the test sample were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2. Parameters such as Tmax, T 1/2 and V d and their mean and standard deviation.
  • samples taken prior to reaching C max should be calculated as zero values when calculating the pharmacokinetic parameters. Samples at the sampling point should be incapable of quantification (BLQ) after C max is reached.
  • the pharmacokinetic parameters of I-10, I-40, INCB024360 were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2, as shown in the following table.
  • the compound of the present invention has good pharmacological absorption and obvious pharmacological absorption effect. Compared with INCB024360, the compound of the present invention has better pharmacokinetic properties and has broad market prospect.
  • the Formula I of the present invention and a pharmaceutically acceptable salt or isomer thereof have a good IDO inhibitory activity, and are suitable for human liver cancer cell lines, human large cell lung cancer cell lines, human ovarian cancer cell lines, and human small populations.
  • the growth of various human tumor cell lines such as cell lung cancer cell line and human non-small cell lung cancer cell line has obvious inhibitory effect, and the drug absorption effect is better.
  • the comprehensive effect of biological evaluation is better than INCB024360, and has higher Medicinal value and broad market prospects.

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Abstract

本发明提供一种新型吲哚胺2,3-双加氧化酶抑制剂及其制备方法、药物组合物，其中R、X基团的定义如说明书所示。同时提供了所述的化合物及其的药学上可接受的盐和异构体在制备与吲哚胺2,3-双加氧化酶(IDO)相关的疾病药物方面的用途，具体而言其在治疗癌症、阿尔茨海默病、抑郁症、白内障等多种重大疾病方面的应用。本发明的化合物活性较好，具有潜在的药用价值和广阔的市场化前景。

Description

新型吲哚胺2,3-双加氧化酶抑制剂
相关申请的交叉引用
本申请要求于2017年6月14日提交中国专利局的申请号为CN201710447020.7、名称为“新型吲哚胺2,3-双加氧化酶抑制剂”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本领域属于抗肿瘤药物领域，具体涉及一种高效的IDO抑制剂及其制备方法和用途。
背景技术
传统的肿瘤疗法都是大分子或细胞疗法，它们是针对细胞表面受体，无法直接调控庞大复杂的免疫细胞内免疫应答体系。肿瘤微环境中有许多免疫抑制分子存在，通过调节这些抑制分子的功能进而改善肿瘤免疫微环境的免疫治疗策略被称为免疫疗法，这个涉及数百个蛋白的调控体系有一些节点可能会和PD-1类似功能或和PD-1抗体有协同作用，而这些靶点最适合用小分子药物调控。因此免疫疗法也被称为是肿瘤治疗史上的一个突破性进展。
吲哚胺2,3-双加氧化酶(indoleamine 2,3-dioxygenase,IDO)是肝脏以外唯一的催化色氨酸沿犬尿氨酸途径分解代谢的限速酶，广泛分布于人和动物的许多组织和细胞中。IDO可通过降低微环境中色氨酸的浓度而达到抑制病原微生物增殖的作用；IDO与神经系统疾病也密切相关,它能降低5-羟色胺的水平而导致抑郁,也可造成脑中喹啉酸等具有神经毒性的代谢产物的累积；一些证据表明，IDO参与免疫耐受的诱导。哺乳动物妊娠、肿瘤耐药性、慢性感染和自身免疫性疾病的研究表明，表达IDO的细胞能抑制T细胞反应，促进耐受性，因此IDO在抑制T细胞免疫和抗肿瘤免疫、诱导母胎免疫耐受和移植物免疫耐受中均发挥重要的代谢性免疫调节作用。目前，IDO是一个重要的药物发现靶标，已经成为抗肿瘤免疫疗法最重要的小分子调控靶点。
目前国内外尚无IDO抑制剂药物上市，在国外进入临床试验分别化合物分别是美国New link Genetics公司的NLG919化合物、Indoximod(NLG-8189)与美国Incyte公司的INCB024360(Epacadostat)化合物，其中Epacadostat和免疫哨卡抑制剂(Yervoy)联合使用显示出了良好疗效，目前Epacadostat已经处于三期临床研究阶段。Epacadostat类似物也处于二期临床阶段，有研究表明二者将成为极具市场潜力的上市IDO抑制剂药物。
Figure PCTCN2017112547-appb-000001
Figure PCTCN2017112547-appb-000002
涉及IDO抑制剂的发明专利申请有WO2016071293、WO2010005958、WO2014066834、WO2016155545、CN 103130735 A等。
目前，IDO抑制剂的研发仍存在较高的技术壁垒，IDO抑制剂作为具有新药靶、新机制的药物，可应用于治疗肿瘤、阿尔茨海默病、抑郁症、白内障等多种重大疾病，具有非常好的市场价值，为了满足目前临床上对IDO调控代谢物的需要，达到更好的肿瘤治疗效果，我们致力于一系列高效低毒的IDO抑制剂的研究开发，这对于医药领域具有重大的意义。
发明内容
本发明的目的在于提供一种新型吲哚胺2,3-双加氧化酶抑制剂及其制备方法。
本发明的另一个目的是提供所述吲哚胺2,3-双加氧化酶抑制剂的药物组合物及其用途。
本发明的目的可以通过以下措施达到：
一种式I所示的化合物及其盐或异构体，
Figure PCTCN2017112547-appb-000003
其中，
R代表氢原子或者
Figure PCTCN2017112547-appb-000004
m代表0～6；
X代表取代或非取代的芳基、芳基联芳基、芳基联杂芳基、杂芳基联杂芳基、
Figure PCTCN2017112547-appb-000005
或者
Figure PCTCN2017112547-appb-000006
其中X中所述的Ar基团独立地任意选自取代或非取代的芳基、芳基联杂芳基、杂芳基；
M独立地任意选自O、S、NH、C1～4烷胺基、
Figure PCTCN2017112547-appb-000007
Y代表取代或非取代的C3～10烯基、C1～10烷基、C3～8环烷基、苯基或者
Figure PCTCN2017112547-appb-000008
中的任意一种；
W代表
Figure PCTCN2017112547-appb-000009
n代表0～6的阿拉伯数字；
所述的X、Ar、Y基团的取代基各自独立地任意选自C1～8烷氧基、卤素、C1～6酯基、氨基、C1～6烷基胺基、三氟甲基、
Figure PCTCN2017112547-appb-000010
Figure PCTCN2017112547-appb-000011
中的一种或几种，其中R代表C1～6烷基。
进一步地，所述的芳基、杂芳基、芳基连芳基、芳基联杂芳基、杂芳基联杂芳基中所涉及的芳基或者杂芳基的环原子个数为5～8。
进一步地,所述的芳基联芳基为苯基联苯基、芳基联杂芳基任意选自苯基联吡嗪基、苯基联咪唑基；杂芳基联杂芳基为5～6元环的含氮杂芳基联5～6元环的含氮杂芳基；
进一步地，所述的杂芳基联杂芳基为嘧啶基联嘧啶基。
在一种方案中，所述的Ar的取代基为F或三氟甲基。
进一步地，Y为取代或非取代的C4～6烷基。
下面给出了本发明的化合物的举例性的、非限制性的具体实例：
Figure PCTCN2017112547-appb-000012
Figure PCTCN2017112547-appb-000013
Figure PCTCN2017112547-appb-000014
Figure PCTCN2017112547-appb-000015
Figure PCTCN2017112547-appb-000016
Figure PCTCN2017112547-appb-000017
及其盐或异构体。
本发明还提供通式I化合物及其盐的制备方法，但不仅限于以下描述的方法。所有的原料都是根据符合通式规律的目标分子的基团特征，并通过这些路线中的方案、有机化学领域普通技术人员熟知的方法制备或者直接购买的。可将用下述方法和合成有机化学领域中已知的合成方法或本领域技术人员意识到的有关改变方法结合在一起，合成本发明化合物。
为了表述清楚，当R的定义不同时，对应的特征更具体的式I分别用式I’和式I”等表示。
式I的制备方案一：
当通式I中所述的R代表氢原子，X的定义与说明书上文定义相同时，其制备方案如下：
Figure PCTCN2017112547-appb-000018
通式I‘化合物及其盐的制备方法包含以下步骤：
取化合物III和化合物II溶解在有机溶剂中，室温下进行反应，后处理得到式I‘化合物。
式I的制备方案二：
当式I中的R代表
Figure PCTCN2017112547-appb-000019
(其中m代表0～6，其他基团定义与说明书上文通式I定义相同)时，式I的制备方案如下所示：
Figure PCTCN2017112547-appb-000020
其中X基团的定义与说明书上文通式I中X的定义相同，式I的制备方案二包含如下步骤：
(1)将化合物I‘(该通式化合物为化合物I通式中R为氢原子的情况)与羰基二咪唑在无机碱的催化作用下反应得到化合物I‘-1；所述的无机碱任意选自碳酸纳、碳酸钾、碳酸铯、碳酸氢纳、碳酸氢钾等。
(2)将化合物I‘-1溶解在有机溶剂中，加入化合物2‘在硼氢化钠或者硼氢化钾的作用下进行反应，得到化合物I‘-2；
(3)将化合物I‘-2溶解在有机溶剂中，加入水合肼、碳酸钾或者碳酸氢钠任意一种碱，进行开环反应，得到化合物I‘-3；
(4)将化合物I‘-3溶解在有机溶剂中，进行脱保护基反应，得到化合物I”(即式I中的R代表
Figure PCTCN2017112547-appb-000021
时的化合物通式)。
进一步地，式I的制备方案二制备可以参照实施例22化合物I-32的方法进行。
本发明的另一个目的是提供中间体化合物III通式的制备方法，如下所示：
为了表述清楚，当取代基的定义不同时，对应的特征更具体的中间体III分别用III-a、III-b、III-c、III-d、III-e、III-f等表示，其制备方案如下。
方案二：
当式I中R代表氢原子，X代表取代或非取代的芳基联芳基、芳基联杂芳基、杂芳基联杂芳基，所述的取代基的定义如说明书上文X基团定义中所述时，制备I的对应的中间体III的方案如下：
Figure PCTCN2017112547-appb-000022
其中P和Q分别独立地代表取代或非取代的芳基或者杂芳基，所述的取代基的定义与说明书上文X基团中的取代基的定义相同。化合物III的制备可以参照实施例3～6的方法进行。
方案二中化合物III-a的制备包含如下步骤：
化合物III-1，化合物III-2在无机碱和钯类催化剂的作用下反应得到。进一步的，无机碱选自碳酸纳、碳酸钾、碳酸铯、碳酸氢纳、碳酸氢钾、氢氧化钠或氢氧化钾中的一种或几种，钯类催化剂选四三苯基磷钯、钯碳、N-杂碳烯钯络合物、氯化钯或其配体、醋酸钯或其配体中的一种或几种。
方案三：
当X代表
Figure PCTCN2017112547-appb-000023
其中Ar基团独立地任意选自取代或非取代的芳基或杂芳基，所述的取代基与说明书上文相同，M代表O原子，Y代表取代或非取代的C3～10烯基、C1～10烷基、C3～8环烷基、苯基或者
Figure PCTCN2017112547-appb-000024
中的任意一种时，中间体III的制备方案如下所示：
Figure PCTCN2017112547-appb-000025
包含如下步骤：
步骤一：选用化合物III-3与化合物III-4在无机碱的作用下反应得到化合物III-5；
步骤二：化合物III-5在还原试剂的作用下还原反应得到III-b。
进一步的，所述的无机碱任意选自碳酸铯、叔丁醇钾、甲醇钠、氢氧化钠或氢氧化钾中的一种或几种，所述的还原剂可以是水合肼、活性炭和FeCl3的组合，也可以在Pd/C催化作用下加氢还原反应。
更进一步的具体反应可以参照实施例7、8、9进行。
方案四：
当Ar基团为芳基联杂芳基时，中间体化合物III的制备参照如下方案进行：
Figure PCTCN2017112547-appb-000026
其中Ar‘为芳基或者杂芳基。
(1)选用化合物III-3-1与化合物III-4在无机碱的作用下反应得到化合物III-5-1；进一步地，该步骤可以参照方案三中的步骤一进行。
(2)化合物III-5-1在还原试剂的作用下还原反应得到化合物III-5-2。进一步地，该步骤可以参照方案三中的步骤二进行。
(3)化合物III-5-2与含有芳基或者杂芳基的硼酸酯类化合物在无机碱和钯类催化剂的作用下反应得到中间体化合物III-c。进一步地，该步骤可以参照方案二的反应类型进行。
如需中间体基团的保护和脱保护反应，可以参照方案一中的方案进行，具体可以参照实施例11或实施例13中的基团保护和脱保护进行。
方案四-1：
当M基团代表O或者-NH时，化合物III-5’和化合物III-5-1’的制备也可以采用含氟的硝基类化合物与二醇类化合物III-4‘或者二胺类化合物III-4”分别在无机碱的作用下反应得到，所述的无机碱可以为叔丁醇钾或者叔丁醇钠等，其制备路线如方案四-1所示，其中Ar和Ar‘的定义与方案四中所述定义相同。具体可参照实施例12中化合物28制备的步骤1 进行或者参照实施例19相应的步骤进行。
Figure PCTCN2017112547-appb-000027
方案五：在一种方案中,当中间体化合物III通式的M代表硫原子时，其制备方案可以参照M代表O原子时进行，可以参照方案三、方案四或者方案四-1中的制备方法，根据目标分子的结构将化合物III-3、III-3-1或者化合物III-4‘中对应的羟基替换为巯基，选用合适的起始化合物进行反应，从而得到当M代表硫原子时的中间体化合物III化合物。具体反应可以参照实施例20或者21进行。
在一种方案中，Y基团上的取代基的引入方法可以参照实施例15的化合物I-43的方案进行。在Y基团取代基为氨基的基础上，与含溴反应官能团的相应取代基化合物进行反应得到。
方案六：
当X代表
Figure PCTCN2017112547-appb-000028
时，其中Ar基团独立地任意选自取代或非取代的芳基、杂芳基、芳基联杂芳基时，所述的取代基与说明书上文相同；M代表
Figure PCTCN2017112547-appb-000029
Y的定义与说明书式I中定义相同，中间体化合物III的制备参照如下方案进行：
Figure PCTCN2017112547-appb-000030
方案六包含如下步骤：
将氨基保护的二胺类化合物5和二羧酸类化合物V加入有机溶剂中，在酰胺化催化剂的作用下，进行酰胺反应，得到化合物IV，然后脱掉保护基得到化合物III-e即可。
进一步地，方案六中的酰胺化反应催化剂任意选自HBTU，HATU,HOBT、EDCI,HOBT、DCC、DIEA中的一种或几种组合。
进一步地，其制备可以参照实施例中化合物I-4的制备进行。
方案七：
当X代表
Figure PCTCN2017112547-appb-000031
其中W代表
Figure PCTCN2017112547-appb-000032
Ar定义与通式I中定义相同时，中间体III的制备可以参照如下方案进行：
Figure PCTCN2017112547-appb-000033
方案七包含如下步骤：
将化合物5溶解在有机溶剂中，低温加入三光气，常温下反应得到中间体IV，然后脱Boc保护基反应得到中间体化合物III-d。进一步地，可参照化合物I-3的制备方法。
方案八：
当X代表
Figure PCTCN2017112547-appb-000034
其中W代表
Figure PCTCN2017112547-appb-000035
(n代表0～6的阿拉伯数字)，Ar定义与通式I中定义相同时，中间体III的制备可以参照如下方案进行：
Figure PCTCN2017112547-appb-000036
方案八
方案八包含如下步骤：
将氨基保护的二胺类化合物5和化合物V-1加入有机溶剂中，在酰胺化催化剂的作用下，进行酰胺反应，得到化合物V-2，然后脱掉保护基得到化合物III-f即可。
进一步地，方案八中的酰胺化反应可参照方案六中的相应步骤进行。
进一步地，其制备可以参照实施例中化合物I-5或I-6的方法进行。
方案九：
当X代表
Figure PCTCN2017112547-appb-000037
其中W代表
Figure PCTCN2017112547-appb-000038
Ar定义与通式I中定义相同时，中间体III的制备可以参照如下方案进行：
将氨基保护的二胺类化合物5和Fmoc-丙氨酸(化合物I-9-1)加入有机溶剂中，在酰胺化催化剂的作用下，进行酰胺反应，得到化合物V-2，然后脱掉保护基即可。进一步地，其制备可以参照实施例中化合物I-9的方法进行。
方案十：
在一种方案中，当中间体化合物III通式的M代表NH、烷基胺、
Figure PCTCN2017112547-appb-000039
时，其制备方案可以参照方案三、方案四或者方案六进行；
另一种情况当中间体化合物III通式的两边的M分别代表O、NH、S、烷基胺中两种不同基团时，其制备方案可以参照M代表O原子时进行，可以参照方案三、方案四或者方案四-1中的制备方法，根据目标分子的结构将化合物III-3、III-3-1或者化合物III-4‘中对应的羟基替换为羟基、NH、巯基、烷基胺中相应的两种不同的基团，选用合适的起始化合物进行反应，从而得到符合目标分子结构特征的两边M基团不对称的中间体III化合物。进一步地，具体反应可以参照实施例27或者28进行。
在上述制备方法中，当包含X、Ar、Y基团或其取代基的化合物因各中间体的制备过程的稳定性需 要而进行基团保护时，需先将相应的中间体进行脱保护基反应，最终得到目标分子化合物。制备化合物的方法如涉及将各种化学基团保护和脱保护。本领域技术人员可容易地确定保护和脱保护的需要以及选择适宜的保护基团。所述的脱保护反应可以在三氟乙酸或者盐酸的催化作用下进行，可以参照实施例10、实施例11、实施例13等类似的脱保护反应来进行。
在一种方案中，上述各方案的中间体或目标分子中包含芳基联杂芳基或芳基联芳基或者杂芳基联杂芳基，可以通过偶联反应得到，具体可以参照方案四的相应步骤进行。
本发明另一方面提供了一种药物组合物，其中含有治疗有效量的式I化合物或其药学上可接受的盐或异构体作为活性成分，以及一种或多种药学上可接受的载体、稀释剂或赋型剂。
该药物组合物优选含有重量比为1％-99％的式I或式II的药学上可接受的盐作为活性成分，更优选含有重量比为5％-85％的活性成分。
除非另有说明，下列用在权利要求书和说明书中的术语有如下含义或特征：
“芳基”表示5至12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳基的非限制性实例有苯基、萘基和蒽基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。芳基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更优选为一个、两个或三个，进而更优选为一个或两个，独立地选自由低级烷基、三卤烷基、卤素、羟基、低级烷氧基、巯基、(低级烷基)硫基、氰基、酰基、硫代酰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、硝基、N-磺酰氨基、S-磺酰氨基。优选地，芳基为5元单环芳基、6元单环芳基。
“杂芳基”表示5至12个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更为优选为一个、两个或三个，进而更为优选一个或两个。未取代的杂芳基地非限制性实例有吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、嘧啶、喹啉、异喹啉、嘌呤、四唑、三嗪和咔唑；优选地，杂芳基为含氮5元单环杂芳基、含氮6元单环杂芳基。
“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。本发明中的烷基包含“亚烷基”。含1－6个碳原子的烷基称为低级烷基。当低级烷基没有取代基时，称其为未取代的低级烷基。更优选的是，烷基是有1-10个碳原子的中等大小的烷基，例如甲基、乙基、亚乙基、丙基、亚丙基、2-丙基、正丁基、异丁基、亚丁基、叔丁基、戊基等。最好是，烷基为有1-5个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、亚丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)，其中烷基的定义与说明书上文定义相同。“烷氧基”优选包括1至10个碳原子的烷氧基，更优选1至6个碳原子的烷氧基；代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“异构体”选自其顺式异构体、反式异构体或者顺反异构体的混合物。
“烯基”，表示2-20个碳原子的含有至少一个碳碳双键的不饱和的脂烃基，包括直链和支链基团。更优选的是，烯基是有2-10个碳原子的中等大小的烯基，进一步优选C2-6烯基。
“卤素”表示氟、氯、溴或碘。
“氨基”表示-NH2。
“羧基”表示-COOH。
“羟基”表示-OH。
“巯基”表示-SH。
“环烷基”表示饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至8个碳原子，最优选环烷基环包含3至6个碳原子，最佳为环丙基。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。
“硝基”表示-NO2。
M代表“烷胺基”时表示
Figure PCTCN2017112547-appb-000040
基团,烷基定义如上文所述，优选C1～4的烷基。
“酯基”表示羧酸衍生物中酯的官能团，-COOR(R一般为烷基等其他非H基团，烷基定义同如上文所述)，例如当其中所含烷基的碳原子个数为1～6时，所述酯基可以简称C1～6酯基。
所述的
Figure PCTCN2017112547-appb-000041
中，Y的两边可以对称，也可以不对称，即与Y相连的两边的M可以代表相同的基团，也可以代表不同的基团，同时对应的Ar，两边可以相同，也可以不相同。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。这类盐用于哺乳动物体内具有安全性、有效性和应有的生物活性。
“药用组合物”指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐、异构体和前药等 与其它的化学成分，例如药学上可接受的载体和赋形剂的混合物。药用组合物的目的是促进化合物对生物体的给药。
“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的载体或稀释剂。
“赋形剂”指的是加入到药用组合物中以进一步便利于给予化合物的惰性物质。赋形剂的实例包括(不局限于)乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。
药物组合物还可含有：润滑剂例如滑石粉、硬脂酸镁和矿物油；湿润剂；乳化剂和悬浮剂；防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯；甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物，以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
说明书中所涉及的化合物简称的中文名如下所示：
HBTU的中文名为苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯；
HATU中文名为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
HOBT中文名为1-羟基苯并三唑
EDCI中文名为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
DCC中文名为二环己基碳二亚胺
DIEA中文名为N,N-二异丙基乙胺
本发明还提供了所述的式I及其药学上可接受的盐或异构体在制备与吲哚胺2,3-双加氧化酶(IDO)相关的疾病药物方面的用途，具体而言其在治疗肿瘤、阿尔茨海默病、抑郁症、白内障等多种重大疾病方面的应用。所述的肿瘤优选为肝癌、肺癌、卵巢癌。
初步药物活性研究结果表明本发明的化合物具有较好的IDO抑制活性，对人肝癌细胞株、人大细胞肺癌细胞株、人卵巢癌细胞株、人小细胞肺癌细胞株、人非小细胞肺癌细胞株等多种人肿瘤细胞株的生长均具有明显的抑制作用，其综合效果比INCB024360更优。药代动力学试验还显示，本发明的化合物药代吸收良好，具有明显的药代吸收效果，与INCB024360相比，本发明化合物在药效相当甚至更高的情况下，具有更好的药代动力学性质，有较大的药用价值和广阔的市场化前景。
具体实施方式
以下实施例进一步描述本发明，但是，这些实施例仅是用于说明本发明，而不是对本发明范围的限制。
实施例1 化合物I-1合成
Figure PCTCN2017112547-appb-000042
取0.3g间苯二胺，加10ml乙酸乙酯溶清，再加0.9g化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到40mg黄色固体I-1。
实施例2 化合物I-2合成
Figure PCTCN2017112547-appb-000043
取0.3g对苯二胺，加10ml乙酸乙酯溶清，再加0.9g化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到30mg黄色固体I-2。
实施例3 化合物I-16合成
Figure PCTCN2017112547-appb-000044
步骤1.取405mg对氨基苯硼酸，400mg 2-氨基-5-溴-3-甲氧基吡嗪，552mg碳酸钾，30mg四三苯基膦钯，10ml DMF及1ml水，置换氮气，升温至100℃反应过夜，TLC检测原料反应完全，降至室温，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到100mg化合物I-16-1。
步骤2.取100mg化合物I-16-1，加10ml DMF溶清，再加190mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到25mg类白色固体I-16。
实施例4 化合物I-17合成
Figure PCTCN2017112547-appb-000045
步骤1.取550mg间氨基苯硼酸，445mg 2-溴-5-氯-4-氟苯胺，552mg碳酸钾，30mg四三苯基膦钯，10ml DMF及1ml水，置换氮气，升温至100℃反应过夜，TLC检测原料基本反应完全，降至室温，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到120mg化合物I-17-1。
步骤2.取120mg化合物I-17-1，加10ml DMF溶清，再加205mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到15mg类白色固体I-17。
实施例5 化合物I-18合成
Figure PCTCN2017112547-appb-000046
步骤1.取550mg间氨基苯硼酸，412mg 3-溴-4-氯苯胺，552mg碳酸钾，30mg四三苯基膦钯，10ml DMF及1ml水，置换氮气，升温至100℃反应过夜，TLC检测原料基本反应完全，降至室温，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到160mg化合物I-18-1。
步骤2.取160mg化合物I-18-1，加10ml DMF溶清，再加300mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到30mg类白色固体I-18。
实施例6 化合物I-19合成
Figure PCTCN2017112547-appb-000047
步骤1.取1.0g 3-溴-4-氯苯胺，3.6g联硼酸频那醇酯，2.0g碳酸钾，300mg四三苯基膦钯，10ml DMF及1ml水，置换氮气，升温至100℃反应过夜，TLC检测原料基本反应完全，降至室温，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到600mg化合物I-19-1。
步骤2.取600mg化合物I-19-1，250mg 3-溴-4-氯苯胺，330mg碳酸钾，30mg四三苯基膦钯，10ml DMF及1ml水，置换氮气，升温至100℃反应过夜，TLC检测原料基本反应完全，降至室温，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到150mg化合物I-19-2。
步骤3.取150mg化合物I-19-2，加10ml DMF溶清，再加200mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到18mg类白色固体I-19。
实施例7 化合物I-7合成
Figure PCTCN2017112547-appb-000048
步骤1.取1.4g对硝基苯酚，1.05g 1,4-二溴丁烷，2.1g碳酸钾，20ml DMF，升温至120℃反应3h，TLC检测原料基本反应完全，降至室温，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.2g化合物I-7-1。
步骤2.取上述1.2g化合物I-7-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加 5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-7-2。
步骤3.取200mg化合物I-7-2，加10ml DMF溶清，再加300mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到28mg类白色固体I-7。
实施例8 化合物I-10合成
Figure PCTCN2017112547-appb-000049
步骤1.取1.6g 2-氟4-硝基苯酚，1.05g 1,4-二溴丁烷，2.1g碳酸钾，20ml DMF，升温至120℃反应3h，TLC检测原料基本反应完全，降至室温，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.3g化合物I-10-1。
步骤2.取上述1.3g化合物I-10-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.8g化合物I-10-2。
步骤3.取200mg化合物I-10-2，加10ml DMF溶清，再加260mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到15mg类白色固体I-10。
实施例9 化合物I-11合成
Figure PCTCN2017112547-appb-000050
步骤1.取1.4g对硝基苯酚，1.0g 1,4-二溴2-丁烯，2.1g碳酸钾，20ml DMF，升温至120℃反应3h，TLC检测原料基本反应完全，降至室温，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.1g化合物I-11-1。
步骤2.取上述1.1g化合物I-11-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.62g化合物I-11-2。
步骤3.取200mg化合物I-11-2，加10ml DMF溶清，再加300mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到12mg类白色固体I-11。
实施例10 化合物I-26合成：
Figure PCTCN2017112547-appb-000051
Figure PCTCN2017112547-appb-000052
步骤1.取2.2g 2-溴4-硝基苯酚，1.05g 1,4-二溴丁烷，2.1g碳酸钾，20ml DMF，升温至120℃反应3h，TLC检测原料基本反应完全，降至室温，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.8g化合物I-26-1。
步骤2.取上述1.8g化合物I-26-1，0.9g三氯化铁，0.4g活性炭，60ml四氢呋喃，升温至80℃后滴加6ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得1.28g化合物I-26-2。
步骤3.取1.28g化合物I-26-2，3.2g 1-(1-乙氧基乙基)-4-吡唑硼酸频哪醇酯，2.4g碳酸钾，300mg四三苯基膦钯，50ml DME及5ml水，置换氮气，升温至100℃反应过夜，TLC检测原料基本反应完全，降至室温，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到0.5g化合物I-26-3。
步骤4.取0.5g化合物I-26-3，加10ml DMF溶清，再加0.37g化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到220mg类白色固体化合物I-26-4。
步骤5.取220mg化合物I-26-4，用10ml四氢呋喃溶清，加入1ml 6mol/L的盐酸溶液，室温反应，TLC检测原料基本反应完全，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到13mg化合物I-26。
实施例11 化合物I-27合成
Figure PCTCN2017112547-appb-000053
Figure PCTCN2017112547-appb-000054
步骤1、步骤2与化合物I-26合成步骤1、步骤2相同。
步骤3.取1.2g化合物I-26-2，4.0g 1-三苯甲基-4-咪唑硼酸频哪醇酯，2.4g碳酸钾，300mg四三苯基膦钯，50ml DME及5ml水，置换氮气，升温至100℃反应过夜，TLC检测原料基本反应完全，降至室温，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到0.8g化合物I-27-1。
步骤4.取0.8g化合物I-27-1，加10ml DMF溶清，再加0.37g化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到250mg类白色固体化合物I-27-2。
步骤5.取250mg化合物I-27-2，用10ml四氢呋喃溶清，加入0.5ml三氟乙酸，室温反应，TLC检测原料基本反应完全，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到16mg化合物I-27。
实施例12 化合物I-28合成：
Figure PCTCN2017112547-appb-000055
步骤1.取1.04g 2-氟-5-硝基三氟甲苯，290mg 1,4-环己二醇，0.55g叔丁醇钾，20ml DMF，室温反应，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.2g化合物I-28-1。
步骤2.取上述1.2g化合物I-28-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-28-2。
步骤3.取200mg化合物I-28-2，加10ml DMF溶清，再加200mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到28mg类白色固体I-28。
实施例13 化合物I-36合成：
Figure PCTCN2017112547-appb-000056
步骤1.取1.6g 3,4-二氟硝基苯，1.05g 2-Boc-氨基-1,4-丁醇，2.2g叔丁醇钾，20ml DMF，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.2g化合物I-36-1。
步骤2.取上述1.2g化合物I-36-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-36-2。
步骤3.取600mg化合物I-36-2，加10ml DMF溶清，再加575mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到280mg类白色固体I-36-3。
步骤4.取280mg化合物I-36-3，用20ml二氯甲烷溶清，加入2ml三氟乙酸，室温反应，TLC检测原料基本反应完全，加入水，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到10mg化合物I-36。
实施例14 化合物I-37合成：
Figure PCTCN2017112547-appb-000057
步骤1.取10ml四氢呋喃，置于0℃下搅拌，分批加入38mg四氢铝锂，135mg化合物I-36-3用5ml四氢呋喃溶清滴加到反应瓶中，TLC检测原料基本反应完全，加饱和氯化铵溶液淬没，然后加入水和乙酸乙酯，分液，有机相用无水硫酸钠干燥后减压至干，柱层析得30mg淡黄色固体化合物I-37。
实施例15 化合物I-43合成：
Figure PCTCN2017112547-appb-000058
步骤1.取100mg化合物I-36，用10ml四氢呋喃溶清，置于0℃下搅拌，加入100mg三乙胺，40mg 5-溴-2,4-二氯嘧啶用5ml四氢呋喃溶清，滴加到反应瓶中，TLC检测原料基本反应完全，加加入水和乙酸乙酯，分液，有机相用无水硫酸钠干燥后减压至干，柱层析得30mg淡黄色固体化合物I-43。
实施例16 化合物I-3合成：
Figure PCTCN2017112547-appb-000059
步骤1.取3.0g N-Boc间苯二胺，加20ml二氯甲烷，低温下加0.72g三光气，移至常温反应。TLC检测原料反应完全，向反应液中加200ml水，用二氯甲烷萃取(50ml*3)，合并有机相，无水硫酸钠干燥后减压至干经柱层析得白色固体1.5g化合物I-3-1。
步骤2.取1.0g化合物I-3-1，加10ml二氯甲烷溶清，滴加2ml三氟乙酸，常温搅拌。TLC检测至原料反应完全，后处理得白色固体0.4g化合物I-3-2。
步骤3.取0.2g化合物I-3-2，加10ml乙酸乙酯溶清，0.4g化合物1，常温搅拌，TLC检测至原料反应完全，滴加1ml TEA，加100水，50ml EA萃取，无水硫酸钠干燥后减压至干，柱层析得30mg淡黄色固体化合物I-3。
实施例17 化合物I-4合成：
Figure PCTCN2017112547-appb-000060
Figure PCTCN2017112547-appb-000061
步骤1.取2.0g N-Boc间苯二胺，0.56g丁二酸，7.2g HBTU，DMF 20ml，1ml三乙胺，常温搅拌5.0h。TLC检测原料反应完全，向反应液加300ml水，大量固体析出，抽虑，得1.5g白色固体化合物I-4-1。
步骤2.取1.5g化合物I-4-1，加20ml DCM溶清，低温加2ml TFA，常温搅拌过夜。TLC检测原料反应完全，有固体析出，加水溶清后用EA萃取一次，水相用氨水调PH＝8～9，大量固体析出，抽虑，得0.3g灰白色固体化合物I-4-2。
步骤3.将所得化合物I-4-2用20ml EA溶清，加入0.4g化合物1，常温搅拌。TLC检测原料基本反应完全，滴加1ml TEA，加100ml水，50ml EA萃取，无水硫酸钠干燥后减压至干，柱层析得30mg白色固体化合物I-4。
实施例18 化合物I-21合成：
Figure PCTCN2017112547-appb-000062
步骤1.取2.0g N-Boc间苯二胺，用10ml四氢呋喃溶清，加入1ml三乙胺，置于0℃下搅拌，加入0.6g4-(氯磺酰)苯甲酸，TLC检测原料反应完全，向反应液加300ml水，大量固体析出，抽虑，得1.5g白色固体化合物I-21-1。
步骤2.取2.0g化合物I-21-1，1.06g N-Boc间苯二胺，3.8g HBTU，DMF 20ml，1ml三乙胺，常温搅拌 5.0h。TLC检测原料反应完全，向反应液加300ml水，大量固体析出，抽虑，得1.5g白色固体化合物I-21-2。
步骤3.取1.5g化合物I-21-2，加20ml DCM溶清，低温加2ml TFA，常温搅拌过夜。TLC检测原料反应完全，有固体析出，加水溶清后用EA萃取一次，水相用氨水调PH＝8～9，大量固体析出，抽虑，得0.3g灰白色固体化合物I-21-3。
步骤4.取600mg化合物I-21-3，加10ml DMF溶清，再加600mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到280mg类白色固体I-21。
实施例19 化合物I-30合成：
Figure PCTCN2017112547-appb-000063
步骤1.取1.6g 3,4-二氟硝基苯,0.44g 1,4-丁二胺，1.1g叔丁醇钾，20ml DMF，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.2g化合物I-30-1。
步骤2.取上述1.2g化合物I-30-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-30-2。
步骤3.取600mg化合物I-30-2，加10ml DMF溶清，再加300mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到12mg类白色固体I-30。
实施例20 化合物I-24合成：
Figure PCTCN2017112547-appb-000064
步骤1.取1.04g 2-氟-5-硝基三氟甲苯，0.66g 1,4-丁二硫醇，0.56g叔丁醇钾，20ml DMF，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.0g化合物I-24-1。
步骤2.取上述1.0g化合物I-24-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-24-2。
步骤3.取600mg化合物I-24-2，加10ml DMF溶清，再加450mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到28mg类白色固体I-24。
实施例21 化合物I-46合成：
Figure PCTCN2017112547-appb-000065
步骤1.取1.05g 2-氟-3-三氟甲基-5-硝基吡啶，0.66g 1,4-丁二硫醇，0.56g叔丁醇钾，20ml DMF，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.1g化合物I-46-1。
步骤2.取上述1.1g化合物I-46-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.5g化合物I-46-2。
步骤3.取500mg化合物I-46-2，加10ml DMF溶清，再加450mg化合物1，室温搅拌，TLC检测原料 反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到28mg类白色固体I-46。
实施例22 化合物I-32合成：
Figure PCTCN2017112547-appb-000066
步骤1.取1.4g化合物I-10，1.05g羰基二咪唑，0.86g碳酸钾，20ml四氢呋喃，升温至50℃反应，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.2g化合 物I-32-1。
步骤2.取上述1.2g化合物I-32-1，60ml四氢呋喃溶清，滴加1.6g化合物2，2.5g硼氢化钠，升温至50℃反应，TLC检测原料基本反应完全，减压旋除大部分溶剂，加入水和乙酸乙酯，分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到0.6g化合物I-32-2。
步骤3.取600mg化合物I-32-2，加10ml四氢呋喃溶清，再加2ml水合肼，室温搅拌，TLC检测原料反应完全，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到280mg化合物I-32-3。
步骤4.取280mg化合物I-32-3，加20ml DCM溶清，低温加2ml TFA，常温搅拌过夜。TLC检测原料反应完全，加水，用氨水调PH＝8～9，加DCM分液，有机相无水硫酸钠干燥后减压至干，经柱层析得到30mg灰白色固体化合物I-32。
实施例23 化合物I-5合成：
Figure PCTCN2017112547-appb-000067
步骤1.取2.0g N-Boc对苯二胺，0.56g 4-(N-叔丁氧羰基氨基)苯甲酸，7.2g HBTU，DMF 20ml，1ml三乙胺，常温搅拌5.0h。TLC检测原料反应完全，向反应液加300ml水，大量固体析出，抽虑，得1.5g白色固体化合物I-5-1。
步骤2.取1.5g化合物I-5-1，加20ml DCM溶清，低温加2ml TFA，常温搅拌过夜。TLC检测原料反应完全，有固体析出，加水溶清后用EA萃取一次，水相用氨水调PH＝8～9，大量固体析出，抽虑，得0.3g灰白色固体化合物I-5-2。
步骤3.将所得化合物I-5-2用20ml EA溶清，加入0.4g化合物1，常温搅拌。TLC检测原料基本反应完全，滴加1ml TEA，加100水，50ml EA萃取，无水硫酸钠干燥后减压至干，柱层析得30mg白色固体 化合物I-5。
实施例24 化合物I-6合成：
Figure PCTCN2017112547-appb-000068
步骤1.取2.0g N-Boc间苯二胺，0.56g 4-(N-叔丁氧羰基氨基)苯乙酸，7.2g HBTU，DMF 20ml，1ml三乙胺，常温搅拌5.0h。TLC检测原料反应完全，向反应液加300ml水，大量固体析出，抽虑，得1.5g白色固体化合物I-6-1。
步骤2.取1.5g化合物I-6-1，加20ml DCM溶清，低温加2ml TFA，常温搅拌过夜。TLC检测原料反应完全，有固体析出，加水溶清后用EA萃取一次，水相用氨水调PH＝8～9，大量固体析出，抽虑，得0.3g灰白色固体化合物I-6-2。
步骤3.将所得化合物I-6-2用20ml EA溶清，加入0.4g化合物1，常温搅拌。TLC检测原料基本反应完全，滴加1ml TEA，加100水，50ml EA萃取，无水硫酸钠干燥后减压至干，柱层析得30mg白色固体化合物I-6。
实施例25 化合物I-9合成：
Figure PCTCN2017112547-appb-000069
Figure PCTCN2017112547-appb-000070
步骤1.取2.0g N-Boc间苯二胺，3.0g Fmoc-丙氨酸，7.2g HBTU，DMF 20ml，1ml三乙胺，室温搅拌5.0h。TLC检测原料反应完全，向反应液加5ml哌啶，脱除Fmoc保护基，反应完后加入水与乙酸乙酯，分液，无水硫酸钠干燥后减压至干，柱层析得0.8g白色固体化合物I-9-1。
步骤2.取0.8g化合物I-9-1，3.0g 3-(N-叔丁氧羰基氨基)苯甲酸，7.2g HBTU，DMF 20ml，1ml三乙胺，室温搅拌5.0h。TLC检测原料反应完全，向反应液加300ml水，大量固体析出，抽虑，得1.5g白色固体化合物I-9-2。
步骤3.取1.5g化合物I-9-2，加20ml DCM溶清，低温加2ml TFA，常温搅拌过夜。TLC检测原料反应完全，有固体析出，加水溶清后用EA萃取一次，水相用氨水调PH＝8～9，大量固体析出，抽虑，得0.3g灰白色固体化合物I-9-3。
步骤3.将所得化合物I-9-3用20ml EA溶清，加入0.4g化合物1，常温搅拌。TLC检测原料基本反应完全，滴加1ml TEA，加100水，50ml EA萃取，无水硫酸钠干燥后减压至干，柱层析得30mg白色固体化合物I-9。
实施例26 化合物I-50合成
Figure PCTCN2017112547-appb-000071
步骤1.化合物I-50-1参考化合物I-30-1合成。
步骤2.取1.2g化合物I-50-1，10ml DMF溶清，置于0℃下，加入0.5g钠氢，反应0.5h后加入2.0g碘甲烷，继续反应2h，TLC检测原料基本反应完全，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到1.15g化合物I-50-2，
步骤3.取上述1.15g化合物I-50-2，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-50-3。
步骤4.取600mg化合物I-50-3，加10ml DMF溶清，再加730mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到35mg类白色固体I-50。
实施例27 化合物I-53合成
Figure PCTCN2017112547-appb-000072
步骤1.取1.6g 3,4-二氟硝基苯，0.45g 4-氨基-1-丁醇，1.1g叔丁醇钾，20ml DMF，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.15g化合物I-53-1。
步骤2.取上述1.15g化合物I-53-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-53-2。
步骤3.取600mg化合物I-53-2，加10ml DMF溶清，再加791mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到30mg类白色固体I-53。
实施例28 化合物I-54合成
Figure PCTCN2017112547-appb-000073
步骤1.取1.6g 3,4-二氟硝基苯，0.53g 4-巯基-1-丁醇，1.1g叔丁醇钾，20ml DMF，TLC检测原料基本反应完全，加入水后，有大量固体析出，抽滤，水淋洗，抽干并烘干，得1.2g化合物I-54-1。
步骤2.取上述1.2g化合物I-54-1，0.6g三氯化铁，0.25g活性炭，60ml四氢呋喃，升温至80℃后滴加5ml水合肼，TLC检测原料基本反应完全，趁热并用硅藻土辅助过滤，保留滤液，减压旋除大部分溶剂，加入20ml甲醇打浆，抽滤，烘干得0.6g化合物I-54-2。
步骤3.取600mg化合物I-54-2，加10ml DMF溶清，再加800mg化合物1，室温搅拌，TLC检测原料反应完全，向反应液滴加几滴三乙胺，加入50ml水，用乙酸乙酯萃取(20ml*3)，合并有机相，无水硫酸钠干燥后减压至干，经柱层析得到45mg类白色固体I-54。
参照上述化合物的制备方法例，在合适的溶剂及反应温度下，通过一系列反应制备得到下列化合物，测试核磁及质谱，包括但不限于下表所示化合物。
Figure PCTCN2017112547-appb-000074
Figure PCTCN2017112547-appb-000075
Figure PCTCN2017112547-appb-000076
Figure PCTCN2017112547-appb-000077
Figure PCTCN2017112547-appb-000078
生物学评价
测试例一 化合物对IDO1的抑制活性测定：
以下结合测试例进一步解释本发明，但这些测试例并非意味着限制本发明，下面是本发明部分化合物在作用浓度为10μM和1μM时对IDO1酶的抑制活性。化合物的结构式如说明书上文实施例所示。
1、材料，试剂盒及仪器
L-抗坏血酸钠(Cat:A4034-100G,SIGMA)
4-(二甲基氨基)苯甲醛(Cat:156477-25g,SIGMA)
三氯乙酸(Cat:T0699-100ML,SIGMA)
L-色氨酸(Cat:T8941-25G,SIGMA)
亚甲基蓝(Cat:M9140-25G,SIGMA)
磷酸二氢钾(Cat:10017618,国药化学试剂)
磷酸氢二钠(Cat:20040618,国药化学试剂)
恒温水槽(Cat:DK-8D,上海精宏实验设备)
多功能酶标仪(Cat:M5,Molecular Devices)
96孔反应板(Cat:3590,costar)
IDO1蛋白酶(市售)
台式酶标仪SpectraMax M5 Microplate Reader(Molecular Devices)
待测化合物：自制
阳性对照药：INCB024360(市售)
2、试剂配制
100mM PBS：
按照3:5混合100mM磷酸氢二钠和100mM磷酸二氢钾，PH6.5
IDO1测定缓冲液：
含有400μML-色氨酸，20mM抗坏血酸盐，20μM亚甲蓝和1000U/ml过氧化氢酶的100mM PBS，PH6.530％三氯乙酸
30％三氯乙酸的ddH2O溶液
Ehrlich试剂
1％(w/v)4-(二甲基氨基)苯甲醛化合物稀释
用DMSO溶解所有化合物，测定时，按需要的浓度对各个化合物进行稀释，每个浓度为复孔，控制DMSO的终浓度为1％。
3.测试方法
a.)配制反应混合物：在100μL IDO1测定缓冲液中加入50nM IDO1和所需浓度的待测化合物。IDO1和测定缓冲液需要预热到37℃。
b.)37℃恒温水槽中反应30min。
c.)加入50μL 30％三氯乙酸。
d.)52℃恒温水槽中反应30min。
e.)室温下12000g离心10min。
f.)混合100μL上清和100μL Ehrlich试剂。
g.)用M5酶标仪在480nm测定吸光。
4.数据分析
抑制率＝(ODpositive―ODsample)/(ODpositive―ODnegative)*100％
5.结果与讨论
本实验检测待测化合物在10μM和1μM时对IDO1酶的抑制活性，每个稀释浓度为复孔测试，控制反应体系的DMSO终浓度为1％，在两个浓度的抑制率分别测试两次，取平均值，实验结果如下表所示，结果表明本申请的化合物对IDO1蛋白酶表现出较好的抑制活性。
本实验检测待测化合物对IDO1酶的抑制活性
  10μM 1μM
化合物编号 Mean Mean
I-1 15.20 1.30
I-2 11.79 1.58
I-3 31.48 3.23
I-4 22.76 9.59
I-5 49.61 18.96
I-6 33.80 15.46
I-7 65.53 25.57
I-8 13.51 3.45
I-9 22.01 6.13
I-10 98.26 83.22
I-11 34.15 20.63
I-12 50.10 11.79
I-13 88.18 27.20
I-14 33.06 13.25
I-15 18.50 0.45
I-16 35.77 0.76
I-17 38.07 3.24
I-18 38.49 3.30
I-19 35.52 0.72
I-20 22.33 12.30
I-21 21.53 8.56
I-22 45.63 13.42
I-23 22.17 9.57
I-24 57.75 34.21
I-25 52.20 11.70
I-26 36.88 13.71
I-27 96.28 47.63
I-28 77.33 65.23
I-29 56.50 21.40
I-30 85.93 66.94
I-31 73.25 48.09
I-32 60.74 28.64
I-33 54.38 22.84
I-34 41.35 12.44
I-35 31.98 12.22
I-36 65.39 33.19
I-37 71.50 61.71
I-38 30.36 11.56
I-39 67.06 34.80
I-40 97.69 72.32
I-41 70.01 61.57
I-42 65.04 37.23
I-43 21.03 11.36
I-44 58.27 31.39
I-45 69.72 39.58
I-46 49.51 26.63
I-47 57.65 33.85
I-48 56.49 27.83
I-49 21.18 9.60
I-50 64.74 38.22
I-51 64.89 42.25
I-52 23.63 11.60
I-53 65.69 28.25
I-54 50.39 27.33
I-55 42.31 25.04
INCB024360 72.20 65.13
结论：试验结果显示，本发明的化合物对IDO具有显著的抑制作用，效果与INCB024360相当甚至更优。
测试例二 化合物体外细胞毒性的IC50值测定
应用CCK-8检测试剂盒检测本申请的化合物对8个肿瘤细胞株的细胞毒性IC50值测试。
1、材料和方法
细胞株:
NCI-H460人大细胞肺癌细胞株(订购于中科院上海细胞资源中心)
BEL-7402人肝癌细胞株(订购于中科院上海细胞资源中心)
SMMC-7721人肝癌细胞株(订购于中科院上海细胞资源中心)
SK-OV-3人卵巢癌细胞株(订购于中科院上海细胞资源中心)
NCI-H446人小细胞肺癌细胞株(订购于中科院上海细胞资源中心)
A549人非小细胞肺癌细胞株(订购于中科院上海细胞资源中心)
HepG2人肝癌细胞株(订购于中科院上海细胞资源中心)
OVCAR-3人卵巢癌细胞株(订购于中科院上海细胞资源中心)
2、试剂和耗材：
Cell Counting Kit-8(Cat#CK04-13，Dojindo)
96孔培养板(Cat#3599，Corning Costar)
培养基和胎牛血清(GIBCO)
台式酶标仪SpectraMax M5 Microplate Reader(Molecular Devices)
3.1培养基的配制
Figure PCTCN2017112547-appb-000079
化合物的制备：
用DMSO稀释本发明化合物使终浓度为10mM。
3.2IC50实验(CCK-8检测)
a)收集对数生长期细胞，计数，用完全培养基重新悬浮细胞，调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定)，接种96孔板，每孔加100μl细胞悬液。细胞在37℃，100％相对湿度，5％CO2培养箱中孵育24小时。
b)用培养基将待测化合物稀释至所设置的相应作用浓度，按25μl/孔加入细胞。化合物的作用终浓度从100μM开始，4倍梯度稀释，10个浓度点，复孔测试。
c)细胞置于37℃，100％相对湿度，5％CO2培养箱中孵育72小时。
d)吸弃培养基，加入含10％CCK-8的完全培养基置于37℃培养箱中孵育1-4小时。
e)轻轻震荡后在SpectraMax M5Microplate Reader上测定450nm波长处的吸光度，以650nm处吸光度作为参比，计算抑制率。
3.3数据处理
按下式计算药物对肿瘤细胞生长的抑制率：肿瘤细胞生长抑制率％＝[(Ac-As)/(Ac-Ab)]×100％
As:样品的OA(细胞+CCK-8+待测化合物)
Ac:阴性对照的OA(细胞+CCK-8+DMSO)
Ab:阳性对照的OA(培养基+CCK-8+DMSO)
运用软件Graphpad Prism 5并采用计算公式log(inhibitor)vs.normalized response进行IC50曲线拟合并计算出IC50值，结果如下表所示：
Figure PCTCN2017112547-appb-000080
结论：本发明化合物对多种人肿瘤细胞株的生长均具有明显的抑制作用，其效果比INCB024360更优。
测试例三 药代动力学评价
对本申请的化合物I-10、I-40和化合物INCB024360进行药代动力学测试，研究其在大鼠体内的药代动力学行为，评价其药代动力学特征。
1、实验动物：从上海西普尔-必凯实验动物有限公司购入36只(雌雄各半)SPF级SD大鼠，其中体检合格、无异常的30只(雌雄各半)健康SD大鼠用于该研究。
2、动物给药
SD大鼠30只(雌雄各半)，按下表进行实验。
Figure PCTCN2017112547-appb-000081
注：*在口服给药前，所有动物禁食过夜(10-14小时)，给药后4小时给食。
3、样品采集与处理
经颈静脉穿刺采血，每个样品采集约0.25mL，肝素钠抗凝，采血时间点如下：
口服给药组：给药前，给药后0.25h，0.5h，1h，2h，4h，6h，8h，24h。
血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)。收集的血浆分析前存放于-80℃。血浆样品由实验机构分析部门采用LC-MS/MS进行分析大鼠血浆中的待测化合物含量，检测物检测的LLOQ均为1ng/mL。
4、药物代谢动力学分析
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数AUC0-t、AUC0-C、MRT0-T、Cmax、Tmax、T1/2和Vd等参数及其平均值和标准差。
对于浓度低于定量下限的样品，在进行药代动力学参数计算时，在达到Cmax以前取样的样品应以零值计算，在达到Cmax以后取样点样品应以无法定量(BLQ)计算。
5、结果与讨论
主要药代动力学参数
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算I-10,I-40,INCB024360的药代动力学参数，见下表。
SD大鼠单次灌胃口服I-10后血浆I-10的主要药代动力学参数
Figure PCTCN2017112547-appb-000082
SD大鼠单次灌胃口服I-40后血浆I-40的主要药代动力学参数
Figure PCTCN2017112547-appb-000083
SD大鼠单次灌胃口服INCB024360后血浆INCB024360的主要药代动力学参数
Figure PCTCN2017112547-appb-000084
结论：本发明化合物的药代吸收良好，具有明显的药代吸收效果，与INCB024360相比，本发明化合物具有更好的药代动力学性质，具有广阔的市场前景。
工业实用性：
根据本发明的实施方案，本发明式I及其药学上可接受的盐或异构体的IDO抑制活性较好，对人肝癌细胞株、人大细胞肺癌细胞株、人卵巢癌细胞株、人小细胞肺癌细胞株、人非小细胞肺癌细胞株等多种人肿瘤细胞株的生长均具有明显的抑制作用，药代吸收效果较好，生物学评价的综合效果比INCB024360更优，具有较高的药用价值和广阔的市场化前景。

Claims (8)

  1. 一种式I所示的化合物及其盐或异构体，
    Figure PCTCN2017112547-appb-100001
    其中，
    R代表氢原子或者
    Figure PCTCN2017112547-appb-100002
    m代表0～6；
    X代表取代或非取代的芳基、芳基联芳基、芳基联杂芳基、杂芳基联杂芳基、
    Figure PCTCN2017112547-appb-100003
    其中X中所述的Ar基团独立地任意选自取代或非取代的芳基、芳基联杂芳基或杂芳基；
    M独立地任意选自O、S、NH、C1～4烷胺基、
    Figure PCTCN2017112547-appb-100004
    Y代表取代或非取代的C3～10烯基、C1～10烷基、C3～8环烷基、苯基或者
    Figure PCTCN2017112547-appb-100005
    中的任意一种；
    W代表
    Figure PCTCN2017112547-appb-100006
    n代表0～6的阿拉伯数字；
    所述的X、Ar和Y基团的取代基各自独立地任意选自C1～8烷氧基、卤素、C1～6酯基、氨基、C1～6烷基胺基、三氟甲基、
    Figure PCTCN2017112547-appb-100007
    Figure PCTCN2017112547-appb-100008
    中的一种或几种，其中R代表C1～6烷基。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于所述的芳基、杂芳基、芳基连芳基、芳基联杂芳基或杂芳基联杂芳基中所涉及的芳基或者杂芳基的环原子个数为5～8。
  3. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于所述的芳基联芳基为苯基联苯基；芳基联杂芳基任意选自苯基联吡嗪基或苯基联咪唑基；杂芳基联杂芳基为5～6元环的含氮杂芳基联5～6元环的含氮杂芳基；所述的杂芳基联杂芳基为嘧啶基联嘧啶基。
  4. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于Y为取代或非取代的C4～6烷基。
  5. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于选自：
    Figure PCTCN2017112547-appb-100009
    Figure PCTCN2017112547-appb-100010
    Figure PCTCN2017112547-appb-100011
    Figure PCTCN2017112547-appb-100012
    Figure PCTCN2017112547-appb-100013
    及其盐或异构体。
  6. 一种药物组合物，其特征在于包含治疗有效量的游离形式或可药用盐形式的权利要求1至5中任意一项所定义的化合物作为活性成分，以及一种或多种药学上可接受的载体、稀释剂或赋型剂。
  7. 含有权利要求1至5中任意一项所定义的化合物在与吲哚胺2,3-双加氧化酶相关的疾病药物中的用途。
  8. 含有权利要求1至6中任意一项所定义的化合物在肿瘤、阿尔茨海默病、抑郁症以及白内障等多种重大疾病方面的应用。
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